Hypertension and diabetes mellitus are risk factors for the onset of cardiovascular events (e.g., myocardial infarction, angina pectoris, congestive heart failure, cerebral infarction, and transient cerebral ischemic attack); the onsets of diabetes mellitus and hypertension often overlap to promote the onset of cardiovascular events and induce serious diseases that may directly lead to death.
It is therefore important to repress the onset and progression of cardiovascular events by performing appropriate treatments on diabetes mellitus and hypertension after identifying their pathologic conditions.
Diabetes mellitus is a metabolic syndrome that involves chronic high blood glucose levels caused by impaired insulin secretion or impaired insulin action in the target organ. The pathologic condition of diabetes mellitus is complex and involves not only abnormal glucose metabolism but also abnormalities in lipid metabolism and the circulatory system. As a consequence, a variety of complications often accompany the progress of diabetes mellitus. Typical complications of diabetes mellitus are diabetic retinopathy, nephropathy, and neuropathy. In particular, diabetic nephropathy causes glomerular excessive filtration or glomerular enlargement in the early stage of onset, followed by decreased cell counts due to inflammation and apoptosis, eventually leading to end-stage renal failure due to glomerular hardening and interstitial fibrosis.
Drugs currently used to treat diabetes mellitus include biguanides, sulfonylureas, glycosidase inhibitors, insulin tolerance ameliorators, dipeptidyl dipeptidase IV (DPP-IV) inhibitors, etc. In addition, sodium-dependent glucose cotransporter-2 (SGLT-2) inhibitors have also been developed as drugs for treating diabetes mellitus via a new mechanism.
The treatment of diabetes mellitus, however, extends so long that side effects often raise a problem and particularly in the case of diabetic nephropathy involving a lowered renal function, many diabetic drugs are difficult to administer in the first place since problems with drug pharmacokinetics (clearance pathway) increase the concern of side effects. Some drugs exhibit a certain level of therapeutic efficacy for diabetic nephropathy if it is at a mild stage but no drugs are yet known that have therapeutic efficacy even after the disease has progressed to the stage of interstitial fibrosis.
Hypertension not only promotes arteriosclerosis but also causes ventricular remodeling due to enlargement of the left ventricle, so it plays a primary role in the onset of cardiovascular events. Therefore, an appropriate hypotensive treatment is required to repress the onset and progression of cardiovascular events and provide improved prognosis for a longer period. To provide an appropriate hypotensive treatment, it is important to have a risk assessment after identifying the pathologic condition and impaired organ of the patient, selecting an appropriate antihypertensive drug, and attaining blood pressure targets. Patients with hypertension complicated by impaired organs as in diabetes mellitus and chronic kidney disease are diagnosed as constituting a group with high risk of cardiovascular events and require strict lowering of blood pressure (Guidelines for the Management of Hypertension 2009 or JSH2009 for short, published by the Japanese Society of Hypertension). Currently, however, it is difficult to attain lower blood pressure targets with single antihypertensive drugs and combination therapy using two or more drugs is required. The problem is that since the treatment is prolonged, side effects due to combined drug use may sometimes occur. For instance, it has been reported that combinations of diuretics and β-blockers adversely affect glycolipid metabolism or that combinations of ACE inhibitors and angiotensin II receptor blockers (ARBs) have high likelihood of transition to end-stage renal failure.
It is therefore necessary to resolve the above-mentioned problems with the combined use of antihypertensive drugs. As of today, no single antihypertensive drugs have been reported that can attain that lower blood pressure targets that are required to repress the onset and progression of cardiovascular events.